The Health Effects Institute

HEI Communication 6
A Partnership to Examine Emerging Health Effects: EC/HEI Workshop on 1,3-Butadiene

Brussels, 29–30 June 1998

INTRODUCTION

As part of its ongoing work to protect health and the environment, Directorate General XI (DG XI) of the European Commission (EC) is charged with proposing legislation to control potentially harmful effects from pollutants. The Commission increasingly has moved to carry out this responsibility by seeking to involve a broad range of stakeholders at different stages of the process.

The Health Effects Institute (HEI) is an independent research organization jointly and equally funded by industry and government to provide independent science on the health effects of air pollution to inform potential regulation.

The materials that follow are the proceedings from a workshop entitled A Partnership to Examine Emerging Health Effects: EC/HEI Workshop on 1,3-Butadiene, held in Brussels, Belgium, on 29–30 June 1998. This was the first in a series of collaborative efforts between the Health Effects Institute, the Commission, and others. The workshop brought together leading European and U.S. researchers funded by Directorate General XII and HEI with representatives of the European Parliament, the World Health Organization, the International Agency for Research on Cancer, the U.S. Environmental Protection Agency, member states, local authorities, industry, nongovernmental organizations, and multiple directorates within the Commission in an open and transparent dialogue to examine underlying science relevant to potential regulation.

Although butadiene is not currently on the list of highest priority pollutants, it was chosen as the subject of the workshop because of recent research results concerning the potential carcinogenicity of butadiene and their possible implications for public health, and because of the request from several member states that butadiene have a higher priority in evaluative and regulatory processes. This workshop was intended as one step to help inform DG XI’s prioritization decisions, and to help inform future research priorities for the Health Effects Institute and Directorate General XII of the European Commission.

HEI wishes to thank the many diverse interests from within and outside government and the scientific community who contributed to this effort.

EXECUTIVE SUMMARY

EC/HEI Workshop on 1,3-Butadiene

Background

1,3-Butadiene (BD) is a chemical used in the manufacture of rubber. It is detect able in urban and suburban air at concentrations ranging from 0.3 ppb to 10 ppb (1 ppb butadiene is equivalent to 0.451 mg/m3), and can be found near industrial sites at concentrations of up to 30 ppb. BD is also found in cigarette smoke and motor vehicle exhaust. A large epidemiologic study found a positive association between employment in the styrene-BD rubber industry and the development of leukemia. In contrast, a study of BD production workers did not show an association with leukemia, al though there was evidence for increased incidence of lymphoma. In addition, several studies have shown that BD and its metabolites can cause genetic damage, such as increased mutations and chromosomal aberrations, while some studies have not.

Because of the paucity of data about BD’s effects in humans and its possible mechanisms of action, scientists have studied these issues in animals. One complication, however, is that the carcinogenicity of BD in animals appears to vary with species. For example, mice develop cancers at multiple sites, including the lung, liver, and heart, with lung tumors increasing in females after chronic exposures to levels as low as 6.25 ppm BD. Life-shortening lymphocytic lymphomas predominate after exposures to levels of BD of 625 ppm or higher. In contrast, rats develop cancer in endocrine organs and only after chronic exposures to high levels of BD (1,000 or 8,000 ppm). Species differences in BD effects may be the result of differences in metabolizing BD to active intermediates: studies have shown that different animal species have different levels of BD metabolites in blood and urine. Notably, the highly mutagenic metabolite 1,2,3,4-diepoxybutane (BDO2) is formed in much larger amounts in mice than in rats. Thus, because it is not clear whether people are more similar to rats or mice in their response to BD, the human risk for cancer from BD cannot easily be extrapolated from information from rodents.

TERMINOLOGY

Systematic name and abbreviation favored in this document Other names and abbreviations used in this document
1,3-butadiene (butadiene),
BD		 ——
1,2-epoxy-3-butene,
BDO		 epoxybutene (EB), 1,2-epoxybutene,
butadiene monoepoxide,
1,3-butadiene monoepoxide (BMO)
1,2,3,4-diepoxybutane,
BDO2		 butadiene diepoxide,
diepoxybutane (DEB)
1,2-dihydroxy-3,4-epoxybutane,
BDO-diol		 3,4-epoxy-1,2-butanediol,
butanediol epoxide (BDE),
butadiene monoepoxide diol,
epoxybutanediol

Other compounds referred to in the text

M I = glutathione conjugate of BDO
M II = glutathione conjugate of BDO-diol
Isoprene = 2-methyl-1,3-butadiene

Human Exposure

Determining the actual level of human exposure to BD is critical to assessing its effects and, ultimately, its risk to people. In the urban atmosphere, the primary source of BD is motor vehicle emissions. There are seasonal patterns of BD exposure; for example, atmospheric concentrations of BD are higher in winter than summer. Most areas of the United Kingdom—one of the few countries in the world with an ambient BD monitoring network—are well below 1 ppb as an annual running average, the level specified in the U.K.’s ambient air quality standard, although areas adjacent to busy roadways occasionally may exceed the standard. Future emissions of BD from mobile sources are expected to decrease. Available data suggest diesel engines may emit relatively more BD than gasoline-fueled vehicles. Much of this information is based on older diesel technology and fuels, however, and may not reflect the current fleet or potentially cleaner fuels.

Butadiene Metabolism

In the body, BD is metabolized by a series of enzymes, including cytochrome P450–dependent monooxygenases, to reactive epoxide metabolites. Detoxification of these intermediates occurs through enzymes such as epoxide hydrolase and glutathione S-transferase. The rates and extent of these enzymatic conversions differ greatly among species. Epoxide metabolites of BD—including 1,2-epoxy-3-butene (BDO), 1,2-dihydroxy-3,4-epoxybutane (BDO-diol), and BDO—can react with DNA and protein such as hemoglobin, and are mutagenic in in vitro assays. BDO2 is the most potent mutagen of the metabolites examined and is carcinogenic when painted on mouse or rat skin. The carcinogenicity of BDO when applied through skin painting on rodents was equivocal. Mice metabolize BD several times faster than rats. The conversion of BD to BDO, or of BDO to BDO, by lung and liver microsomes occurs faster in mice than in humans and rats. Conversely, the elimination of BDO and BDO2 through action of liver microsomal epoxide hydrolase is fastest in humans and slowest in mice. Detoxification through glutathione S-transferase occurs fastest in mice and slowest in humans. Pharmacokinetic models predict that humans will have lower levels of BDO and BDO2 as compared with the levels in rodents following equivalent exposures to BD. Furthermore, examining adducts between hemoglobin and BDO indicate there is a low body burden of BDO in humans compared with the level in mice or rats under similar conditions. Thus, it is clear that there are differences in how mice, rats, and humans metabolize BD. The exact nature of these differences is emerging in current research, but is not yet fully understood.

Butadiene Genotoxicity

The three epoxide metabolites of BD—BDO, BDO2, and BDO-diol—are all able to react co valently with proteins and DNA, and thus have the potential to cause genetic damage. BD is mutagenic in various test systems, including in vitro exposures of prokaryotes and eukaryotes supplied with a metabolism element and in vivo exposures of rats and mice. As with cancer induction and metabolism, there are differences among species in the mutagenicity of BD. For example, inhaled BD is 5-fold more potent in causing mutation in mice than it is in rats. The magnitude of the difference between rats and mice, however, is much lower than would be expected based on metabolism differences. Of the three epoxide metabolites, BDO2 is the most potent, causing mutations at concentrations 40- to 400-fold lower than mutagenic concentrations of BDO or BDO-diol. BDO2 has also been shown to cause deletions within the DNA of exposed cells or animals.

When mutations and chromosomal changes are examined in people occupationally exposed to BD, some studies show increases for exposed workers but others do not. These findings may be explained, in part, by methodological differences. Differences in metabolic capability in individual people may influence whether they are susceptible to genetic effects of BD.

In the mouse, BD is a potent clastogenic agent, producing chromosome breaks and aberrations. These aberrations can be seen in cells present in many organs of inhalation-exposed animals, including bone marrow, spleen, lung, and testis. Although the clastogenic effectiveness of BD metabolites varies across organs and species, BDO2 is the most potent metabolite, followed by BDO and then BDO-diol. The consequences of clastogenic action by BD in the mouse appears to include heritable translocations. BD and metabolites may also interfere with chromosome segregation. In contrast, BD is not clastogenic in the bone marrow of rats, nor does it induce dominant lethal mutations. When cells of humans exposed to BD are examined, evidence of clastogenicity is observed in lymphocytes.

The clastogenic potency of BD and its metabolites is modulated by glutathione S-transferase T1, an enzyme involved in the detoxifying pathway. Some people do not express this enzyme. These individuals, when exposed to BD, have a greater number of cells showing sister-chromatid exchanges and chromosomal aberrations than BD-exposed people who do express this enzyme.

Epidemiologic Studies of Butadiene

The epidemiologic data on BD are not completely consistent. The most informative data are from a large, carefully conducted study of exposed workers involved in the manufacture of styrene-BD rubber, where an exposure-related increase in the risk of leukemia is observed. The association of BD with increased incidence of other lymphohem ato poietic neoplasms is inconsistent among different studies of this cohort. The styrene-BD rubber workers were also exposed to chemicals other than BD. Results from the only other large cohort study, among BD production workers, showed a small but significant increase in lymphoma. The incidence of lymphoma in this cohort was inversely proportional to the length of employment.

Risk Characterization, Risk Assessment, and Regulation of Butadiene

Potential hazards from exposure to BD include cancer, heritable mutation, and reproductive endpoints. There are still questions about whether the appropriate exposure metric should be cumulative or peak exposures, as well as questions about which metabolites are of concern, what the mechanism of toxicity is, what the dose-response relationship is, and whether quantitative extrapolation should start from rat or mouse data.

A crucial issue is whether BD is a human carcinogen. This assessment is the starting point for both regulatory action and further discussion of science and policy issues. Demonstration of carcinogenic activity in a nonhuman species is not necessarily sufficient to establish evidence of human carcinogenicity. Epidemiologic evidence, however, can be sufficient to define an agent as a known human carcinogen. In the absence of definitive epidemiologic data, an agent may still be classified as a known human carcinogen if it has been shown to be carcinogenic in a nonhuman species, and if there is supporting information showing that the biological mechanisms involved may be similar in people.

A number of national and international agencies are currently undertaking risk assessments for BD, attempting to interpret the existing data to determine whether BD is a human carcinogen and how potent it might be.

Within the European Union (EU), there has been a risk assessment under the Existing Substances Regulation with the U.K. Health and Safety Executive acting as the rapporteur for the rest of the EU. The U.K. regulatory agency has concluded that, although uncertainties still exist about risk, there is concern, and exposure should be controlled to the lowest practical level. BD is therefore classified as a Category 2 carcinogen (substances that should be regarded as if they are carcinogenic to humans).

The U.K. Department of Environment established an air quality standard for BD in the U.K. of 1 ppb as a running annual average. EC Directorate-General V, through their Scientific Committee on Occupational Exposure Limits (SCOEL), are currently determining appropriate workplace exposures for the EU.

The International Agency for Research on Cancer (IARC) recently met to discuss the classification of BD, which had previously been classified as a "probable human carcinogen." After reviewing the evidence, IARC has continued to classify BD as a "probable human carcinogen" (IARC Class 2A), and other agencies—such as the EC Directorate-General XI, Health Canada, and the U.S. Environmental Protection Agency (U.S. EPA)—are currently considering the issue.

The U.S. Environmental Protection Agency classified BD as a "probable human carcinogen" in 1985, and a change to "known human carcinogen" is currently being considered. In addition to a quantitative assessment for the risk of cancer, the U.S. EPA has also estimated noncancer risks. Under the U.S. Occupational Safety and Health Act, occupational limits to BD are set at 1 ppm as a permissible exposure limit (time-weighted average), 5 ppm as a short-term exposure limit (15 minutes), and 0.5 ppm as an action level. The U.S. National Institute for Environmental Health Sciences has listed BD as a "known human carcinogen."

Health Canada is in the process of completing a health assessment for BD as required for Priority Substances under the Canadian Environmental Protection Act. The agency is considering a classification of "highly likely to be carcinogenic in humans" in this health assessment, and has included a calculation of cancer potency as derived from human and animal data as well as a benchmark concentration for noncancer health effects.

Research Needs

Additional research is needed in three areas. Studies to clarify the epidemiologic data will help determine the contribution of confounding exposures and allow extension of the results from the rubber industry to other industries. Further studies on cross-species comparisons should include research aimed at a better understanding of metabolism pathways in different species. Finally, additional research is needed to identify the active carcinogenic metabolite in different species, and to determine whether this metabolite is formed in appreciable amounts in people. Research in these areas may produce definitive results in a relatively short span of time.

Conclusions

AGENDA

Day One: 29 June 1998

(Morning Chair: Prudencio Perera, European Commission, DG XI)

10:00 am Welcome

Prudencio Perera (European Commission, DG XI)
Canice Nolan (European Commission, DG XII)
Daniel Greenbaum (Health Effects Institute)

10:15 am The DG XI Approach to Air Toxics and 1,3-Butadiene

Lynne Edwards (European Commission, DG XI)

10:30 am Introduction to 1,3-Butadiene

Rogene Henderson (Lovelace Respiratory Research Institute, USA)

11:00 am Ambient Concentrations of 1,3-Butadiene in the UK

Geoffrey Dollard (AEA Technologies, UK)

11:30 am Discussion

12:00 pm Lunch Break

(Afternoon Chairs: Canice Nolan, European Commission, DG XII; and Daniel Greenbaum, HEI)

1:15 pm Metabolism of 1,3-Butadiene

Johannes Filser (GSF Institute of Toxicology, Germany)

2:00 pm Genotoxicity of 1,3-Butadiene

Richard Albertini (University of Vermont, USA)
Francesca Pacchierotti (ENEA, CRE Casaccia, Italy)

3:15 pm Epidemiology of 1,3-Butadiene

Paolo Boffetta (IARC, France)

4:00 pm Introduction to Poster Session

Daniel Greenbaum (HEI)

4:10 pm Break

4:20 pm Poster Session of Butadiene Research and Informal Discussion

European and United States Investigators:

Richard Albertini, University of Vermont, USA
Diana Anderson, BIBRA International, UK
Ian Blair, University of Pennsylvania, USA
James Bond, Chemical Industry Institute for Toxicology, USA
Johannes Filser, GSF Institute of Toxicology, Germany
Rogene Henderson, Lovelace Respiratory Research Institute, USA
Gunter Neumann, University of Würzburg, Germany
Francesca Pacchierotti, ENEA, CRE Casaccia, Italy
Kimmo Peltonen, Finnish Institute of Occupational Health
Leslie Recio, Chemical Industry Institute for Toxicology, USA
Radim Šrám, Academy of Science of the Czech Republic, Czech Republic
James Swenberg, University of North Carolina at Chapel Hill, USA
A. D. Tates, University of Leiden, The Netherlands
Vernon Walker, New York State Dept. of Health, Wadsworth Center, USA

6:15 pm Adjourn for day

Day Two: 30 June 1998
(Chair: Daniel Greenbaum, HEI)

9:30 am Summary of Day One and Issues to Consider for Regulating Risks from 1,3-Butadiene

Seymour Garte (New York University, USA)

10:30 am Panel: Butadiene Risk Assessment in the Regulatory Framework

Michael Penman (Exxon Europe, UK; ECETOC)
Sharon Munn (European Chemicals Bureau, Joint Research Council)
Isla Brooke (UK Health and Safety Executive, UK)
Aparna Koppikar (Environmental Protection Agency, USA)
Kathryn Hughes (Health Canada)

12:00 pm Lunch

1:30 pm Panel: The Broader Picture: Setting Priorities Among Chemicals

Gail Charnley (The Weinberg Group, formerly Presidential/Congressional
    Commission on Risk Assessment and Risk Management, USA)
Robert Maynard (Department of Health, UK)
Rolaf van Leeuwen (World Health Organization, The Netherlands)

2:30 pm Summary and discussion

3:00 pm Adjourn

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